Findings from both clinical and laboratory studies indicate that females and males respond differently to the psychostimulant, methamphetamine. The exact basis for these gender differences is not known; however, an important variable which may contribute to this differential responding may be the gonadal steroid hormone, estrogen. Estrogen levels are several fold greater in females, and one of the primary brain target sites of methamphetamine (nigrostriatal dopaminergic system) is markedly influenced by estrogen. Accordingly, our working hypothesis is that estrogen may represent a major factor which underlies the differences observed in methamphetamine responses between males and females. To test this hypothesis, in Part 1 of the proposal two sets of experiments are planned in which estrogen and anti-estrogen levels will be manipulated within male and female mice and resultant effects upon methamphetamine responses evaluated. In this way, it will be possible to specifically isolate and assess the influence of estrogen upon methamphetamine responses. In Part 2, some of the mechanisms by which this estrogen/anti-estrogen modulation of methamphetamine occurs will be examined. To accomplish this goal the effects of direct infusions of estrogen/anti-estrogen and methamphetamine within the brains of male and female mice will be surveyed. Taken together, these experiments will enable us to: 1) Determine whether estrogen is the critical variable contributing to the gender differences observed to methamphetamine, 2) Establish whether this estrogen can exert these effects in the male and 3) Understand some of the mechanisms by which estrogen may act within the brain of females and males.